Showing posts with label Off-label. Show all posts
Showing posts with label Off-label. Show all posts

Friday 10 July 2015

Clinical Investigation vs Off-Label Treatment for Autism

Antonio Hardan, the psychiatrist at the Stanford School of Medicine, has published another paper.  Hardan is interesting, he is a clinician rather than a rocket scientist, but he gets involved in a very wide variety of clinical trials, usually of existing drugs that might be effective in autism.

In his latest paper, this time about Glutamatergic Dysfunction in Autism, he highlights the problems with clinical trials:-

·        Heterogeneity of autism

·        Subjective rating scales rather than biological measures.

In other words there is no single autism and there is no good way to reliably measure the efficacy of any drug tested on it.  Consider what that really means.

Hardan really should know about this, just look at the clinical trials he has been involved in:-

So why bother with Clinical Trials?

This may sound like a very unscientific question, but perhaps it is not.  A couple of years ago Roche pulled the plug on Arbaclofen, because it “failed” in its autism clinical trial.  Many parents thought it worked.  Now the Simons Foundation has acquired the rights to the drug and is restarting trials.  How many other trial drugs were prematurely brushed aside?

Many years ago the hormone secretin was put forward as a therapy for autism, particularly for people with GI problems.  Several expensive clinical trials later, it was determined to be ineffective.  But some people continued to rave about it.  Where they all deluded?

The very expensive IVIG therapy has also been put forward as a wonder therapy for autism.  The critics highlight that in studies 90% of people do not benefit and therefore the therapy has little value.  But what if you are in 10% that do respond very well?

Intravenous immunoglobulin treatment of children with autism.


Since autism has been associated with immunologic abnormalities suggesting an autoimmune cause of autistic symptoms in a subset of patients, this study was undertaken to investigate whether intravenous immunoglobulin (i.v.Ig) would improve autistic symptoms. Ten autistic children with immunologic abnormalities, demonstrated on blood tests, were enrolled in this study. Their ages ranged from 4 to 17 years, with two girls and eight boys. Eight children (1 female and 7 male) historically had undergone autistic regression. Intravenous immunoglobulin, 200 to 400 mg/kg, was administered every 6 weeks for an intended treatment program of four infusions. In five children, there was no detectable change in behavior during the treatment program. In four children, there was a mild improvement noted in attention span and hyperactivity. In none of these children did the parents feel that the improvement was sufficient to warrant further continuation of the infusions beyond the termination of the program. Only in one child was there a very significant improvement, with almost total amelioration of autistic symptoms over the time period of the four infusions. Once the treatment program was completed, this child gradually deteriorated over a 5-month time period and fully reverted to his previous autistic state. In this treatment program, five children had no response to intravenous immunoglobulin. In the four children who showed mild improvements, those improvements may simply have been due to nonspecific effects of physician intervention and parental expectation (ie, placebo effect). However, in one child there was a very significant amelioration of autistic symptoms. There were no distinguishing historic or laboratory features in this child who improved. Given a positive response rate of only 10% in this study, along with the high economic costs of the immunologic evaluations and the intravenous immunoglobulin treatments, the use of intravenous immunoglobulin to treat autistic children should be undertaken only with great caution, and only under formal research protocols.

Just in this blog, which is amateur and not intended as a rigorous scientific review, we have seen numerous “rare” conditions that lead to “autism” that are actually treatable.

If you add up all these “rare” conditions you get a sizeable proportion of all the autism, diagnosed in those under four years old (i.e. more severe autism).

Clinical Investigations

If you accept that the initial autism diagnosis really tells very little, then you are left, like Hardan, testing all sorts of clever ideas on a trial group of kids who may have one to several, of thousands of discrete dysfunctions (CNVs etc.).

Then if you get a 10% response rate, you are doing great.

If you target something like oxidative stress, that is caused by hundreds of those thousands of discrete dysfunctions (CNVs etc.), then your odds of success shoot up.  This was the case in Hardan’s trial of N-acetyl cysteine.

Hardan is now going to trial oxytocin on kids with autism, but this idea has already been well and truly “trashed” by highly respected mainstream doctors.  They do this because they think autism is something easy to define and measure like high blood pressure.  If it is therapeutic in 10% of cases, that is great.

Quacks, Off-label and Clinical Investigations

I think it is great that Hardan can try all these drugs at Stanford and nobody even thinks of calling him a quack.  The same applies to a small number of inquisitive doctors at Johns Hopkins and Boston Children’s Hospital.

It would be interesting to know how Hardan treats his patients with ASD, who are not enrolled in a clinical trial.  Does he prescribe off-label? 

It is clear that most doctors in developed countries will run a mile/kilometer at the idea of treating somebody off label.  They fear being struck off/sued/ridiculed.

We had the UK pediatrician commenting on this blog that Baclofen was effective in 70+% of her/his patients with anxiety plus Asperger’s, but did not feel happy to continue prescribing it without some supporting evidence from elsewhere.  The fact that it was safe and effective was not enough.

Many of the tiny number of off-label doctors really do look like quacks to me, so I can understand the concern of mainstream doctors not to want to be associated with them.

What is the, scientifically well-briefed, parent supposed to do? (if self-treating is not an option)

I think there should be a way where you can enroll your child in a “clinical investigation”, where you accept that all the treatments are experimental and therefore have a higher level of risk than normal.  You waive your right to sue the doctor, or the hospital.  You can opt out of up to 10% of the therapies, based on valid concern.  For example, you might think IVIG is not safe.

You then enter a program in which all your child’s data can be used for research purposes.  So you agree to have to have EEGs, scans, genetic testing, spinal tap/lumbar puncture, blood tests, urine tests, hair tests etc.

The child is completely profiled and material is stored for possible further analysis later.

All known tests are then carried out, even obscure things like biotin deficiency, creatine deficiency and those amino acids we saw that triggered rare autism.

Then you go through all of the therapies known to be effective in some people.  So it includes memantine, IVIG,  donepezil, bumetanide, oxytocin, propranolol, baclofen, arbaclofen, even Zyrtec, NAC, D-Cycloserine, carnosine, carnitine, pancreatic enzymes, probiotic bacteria  etc.

The whole process would take a year.  If you treated 1,000 children you would then have a wealth of data.

You might have individually rare disorders totaling 15% of cases and then several clusters where the same drugs were effective in sizeable groups of children.  Then you would be able to look back in the data for the biomarkers of each cluster.

Then you would write a smartphone app for doctors to treat autism.  They would input the various biomarkers requested and out would come the suggested drug therapy recommendation(s).  So it would be a “guided off-label” approach where the doctor knows that the recommendations are “scientifically supported” but may not be perfect.

We just need the Simons Foundation to sponsor it! 

If you think it might be too expensive, just remember that at the recent international autism conference in Utah, there were 2,000 scientists and researchers in attendance. What exactly have they achieved, in practical terms, in the last 10 years and are likely to achieve in the next 10 years?

It does seem that some view success as diagnosing ever more people with "autism", so that they can receive "services", when they really should be diagnosing specific biological dysfunctions.

It is not an easy task, but you do not need 2,000 researchers.  You just need 20 pragmatic people to review the data and make a decision tree showing how to choose the 5 drugs most likely to help a particular person, based on their specific biomarkers.  

I guess that would leave 1,980 people with not much to do. 

Sunday 24 August 2014

The Cost of Approving an Old Generic Drug as a New Autism Drug

Some readers of this blog are commenting how hard it is to obtain prescription only drugs for “off-label” use in autism.

None of the drugs mentioned in this blog are actually approved for use in autism.  There is some science showing that they might be effective, but there is no mention of autism on the “label” approved by the regulator.

This means that your doctor will not know how to prescribe it and your insurer will not want to pay for it.

So how do I access these drugs?

This is a frequent question.  In theory you do not need to wait for the drug to be approved, you can apply to the national drug agency in your home country for permission to use a drug based on the experimental use that showed it might be effective.

Better still, in many countries like the USA, doctors are not banned from prescribing “off-label” drugs.  If the doctor follows the new research, he is permitted to apply it on his own patients.  If he does it recklessly, he might eventually lose his license.

In cancer therapy, many drugs are used off-label.

Why not just approve a new use for an old drug?

This would seem an obvious question and this is what is being done with bumetanide, one of drugs described in this blog.

The problem is the cost and the time taken: EUR 4 million  (USD 5 million) and four years.

As you can see below, in the case of Bumetanide, the French Government will contribute EUR 1 million and it appears the Simons Foundation another EUR 1.5 million.

Since Bumetanide is available today as a cheap generic drug, they cannot really ever get their money back.  Only if they modified the molecule slightly, patented it, and got that new drug approved could they recoup their USD 5 million, which would then be even more, since they would have even higher costs.

The last I heard, Bumetanide will only be approved for autism in Europe, not the USA, due to cost issues.

So with this kind of financial logic, you can see why off-label uses of old generic drugs are likely to stay off-label.  

Best find yourself an off-label doctor.

Sunday 9 February 2014

Who Pays the Piper? Off-Label or Polypill

It seems that autism is not the only “untreatable disease”, that does appear to be treatable.  At least twenty years ago, one apparently related condition was extensively treated off-label.  I am reading an intriguing book about the off-label treatment of Fibromyalgia in the 80s and 90s.


In medical-speak “off-label” is when a drug is use for a purpose it was never actually approved for.  If you have straight forward diseases, you would never need to use a drug “off label”.

In some countries off-label prescribing by doctors is totally discouraged, in others, it is quite common.
The problem occurs when it comes to paying for expensive drugs and, of course, who is to blame if things go wrong.
Since many drug discoveries are actually stumbled upon by chance, off-label drug use is not as crazy as it may sound.

Socialized Healthcare, Private Insurance and Lawsuits
In the developed world, healthcare is provided either via some kind of private insurance as in the US, or it is via the State, as in Europe.  If your insurer is unwilling to pay for off-label treatments, you will not get them (unless you pay yourself).  In the UK, if the treatment is not endorsed by NICE (in effect, the State), you are not going to get it.  In the old days, the doctor might have been willing to try some off-label drugs, but now they are likely to be more worried about being struck of the medical register for malpractice, or, in the US, being sued.

So, all over the world off-label prescribing is getting rarer.  Certain states in the US are more liberal, Florida I believe is one.
Your healthcare is really in the hands of big brother; in general, this is not a bad thing.  If you have some rare, “untreatable” condition, then the problems start.  Even if you know what off-label drug you want, you will struggle to get it.  You will even struggle to get any unusual blood tests done.

In some countries the system is much more liberal.  If you want to measure potassium in your blood or maybe IGF-1 or serotonin, the process is akin to having your dry cleaning done.  You pay and it gets done.

Off-Label in the US
Before insurers tightening things up in the 1980s, doctors in the US seemingly were able to prescribe pretty much what they wanted.  If you read about some of the things prescribed for severer cases of Fibromyalgia, you would be amazed at the things they used (IVIG, Baclofen, Oxytocin etc.) and how the underlying principle was one of trial and error.

Due to the unusual position of osteopathic medicine in the US, where osteopaths have the same drug prescribing rights as medical doctors, there are many “alternative” doctors practising what they call “holistic medicine”.  Then there is a small army of DAN doctors, some of whom are medical doctors and some are not.  You also have a large number of chiropractors in the US; graduates of chiropractic schools receive the degree Doctor of Chiropractic (DC), as I was told by a reader of this blog, US  Chiropractors do not prescribe drugs, but they do treat kids with autism (I am not sure how).
So it looks like, while the golden days are over, off-label drug prescribing is alive and well in the US.

From Off-Label to On-Label
You would think that once an off-label therapy gets established, it would be able to transition to on-label, and become an accepted mainstream therapy.  This does not happen very often.  The doctors using off-label widely, are seen as quacks by some established doctors and by much of the public.  If they are treating unusual, hard to define conditions, it is hard to carry out controlled clinical trials, and nobody has an interest to pay for them anyway.

So, off-label tends to stay off-label and for most people, untreatable conditions remain untreatable.

I am wary of my ideas being seen as risky, off-label, quack nonsense.  They certainly are off-label uses.

I think you should be able to transition from off-label to on-label.  If the disease is just a cluster of symptoms and pathologies, it will be hard to identify the sub-type for which the therapy is effective.  This applies to both autism and indeed fibromyalgia.
To move away from the very unscientific, and indeed wasteful, trial and error approach, you have to be able to use reliable biomarkers or diagnostic tests.  You would have to prove to a very cynical public, that you are not spouting nonsense.

Then faced with a therapy which can be shown effective consistently, albeit for a rare, very well defined, condition (based on blood tests etc.), there is no good reason why the therapy should not go on-label.
The question now with the Polypill is to be able to identify with >75% certainly for whom it will be effective.  I also need to understand, and indeed predict, when it might stop working.  This may sound very strange, but can happen.

Predicting when it might stop working, as well as suggesting what to do should that occur, makes things tricky. To do it perfectly you would really need the old school off-label doctor, and a vast amount of consultation time, that will not be available.
I live in a country where access to lab tests is very open and they are inexpensive, so I have come up with a testing strategy to accompany the Polypill, using tests that are inexpensive.

The idea of the tests is twofold; to identify the sub-group of children who will benefit from the Polypill therapy and to establish a baseline of markers to later understand any cases, should the Polypill “stop working”

Blood tests
·        IGF-1

·        Serotonin

·        Free T3

·        Cholesterol LDL & HDL

·        Histamine

·        Inflammatory markers CRP and   IL-6

·        Potassium

I would also use the TRH stimulation test, except it is not available where I live and requires several blood draws.  It shows central hypothyroidism to be common in autism (as it is, interestingly, in fibromyalgia).
I am expecting any loss in efficacy of the Polypill to be accompanied by a surge in histamine and/or the easy to measure inflammatory markers, C - reactive protein (CRP) and Interleukin-6.

The trials would take place in winter (no pollen) and would exclude people with food allergies, digestive disorders, IBD, IBS, pancreatic enzyme deficiency etc.  The trial would be exclusively for early onset autism, no regression.
People with seizures would be very welcome and might form a separate subgroup within the test; I expect the incidence of seizure and epilepsy to be reduced by the Polypill.

Having created a trial based on children with elevated IGF-1, Serotonin, Free T3 and Cholesterol, I would then continue to measure all the above indicators on a monthly basis.

Assessing Success
Since the Polypill has several active ingredients, I would expect a marked reduction in autistic behaviours, based on any established autism rating scale.  I would expect parents, teachers and therapists to be really impressed by the effect.

Using the above screening biomarkers to select the trial group, I would hope to achieve a successful outcome in a great majority of cases.  This success rate has to be measured.  Perhaps the screening exclusions and biomarkers are too restrictive, or not restrictive enough.  If it was 100% effective, they should be relaxed; if it was 50% they should be tightened.
What intrigues me are the cases where the Polypill may stop working after a period of success.  If this is understood, it will be another step in understanding the dynamic nature of autism.  If the loss in effect can be correlated to an increase in histamine, in some cases, I will know what to do.  If in some cases CRP and IL-6 rise but histamine and serotonin do not, we would know that the immune system had been activated, but mast cells have not degranulated.  In these cases it would require the, currently under development, “Autism Toolkit”, to provide some immuno-modulatory therapy.

Just as abruptly as the Polypill might stop working in a child, I expect it will start working again, when the external stimulation (whatever it might be) has been withdrawn.
In children who have a permanent state of over-activation of their immune system, they should have sky high CRP and IL-6 and the Polypill will never start to work in the first place.  High inflammatory markers are seen in regressive autism, according to Ashwood, who is on my Dean’s List.

Having rationalised my objectives, I am finalizing my initial submission to the European Medicines Agency, to see whether the Polypill should remain Peter’s off-label curiosity, or become an Orphan Drug, to share with others.